The variability of human immunodeficiency virus (HIV) makes it difficult to develop effective vaccines directly targeting viral proteins. An alternative strategy is to focus immune responses against polymorphic cellular proteins incorporated into viruses as they bud from infected cells. Immune recognition of cellular proteins derived from members of the same species is referred to as alloimmunity. Early HIV vaccine studies in macaques observed impressive levels of protection from simian immunodeficiency virus (SIV) infection. It was quickly discovered, though, that the key components were human proteins used to prepare the vaccines rather than the viral antigens. This suggests that human proteins incorporated into the viral envelope may present an Achilles heel for AIDS viruses and provide an opportunity for vaccine-induced alloimmune responses to prevent virus transmission. One of the primary human proteins incorporated into the virus are major histocompatibility complex (MHC) molecules. MHC molecules are 10X more abundant on the surface of HIV virus particles than viral envelope proteins, suggesting that there are ample targets on the virus for anti-MHC antibodies to bind and exert an antiviral effect. Alloreactive cellular immune responses may provide an important second line of defense against viral infection. Women immunized with their partners' cells display increased production of antiviral factors by T cells that can block HIV infection. This indicates that immunization with polymorphic cellular proteins may create an environment where CD4+ T cells are less susceptible to HIV infection. Controlled studies of alloimmunity are difficult. In this proposal we will leverage the unique genetics of Mauritian cynomolgus macaques (MCM) to test the hypothesis that alloreactive immune responses can inhibit the acquisition of SIV infection. MCM have only a small number of expressed MHC molecules making it possible to incorporate defined MHC molecules in the SIV virions, specifically target alloimmune responses against defined host molecules, and characterize proteins on the SIV stock. We will test this hypothesis with the following Specific Aim: AIM1: Assess the ability of alloreactive immune responses to protect MCM from SIV infection. We will alloimmunize MCM with cells from other MCM that express distinct MHC molecules. The alloimmunized MCM, along with mock vaccinated and unvaccinated controls, will be mucosally challenged with SIV grown in the cells of the MCM used for immunization. This proposal will assess the prophylactic potential of allogeneic immune responses against host polymorphic molecules on the surface of virions. If successful, it will provide an innovative, practical, and safe strategy for circumventing the challenge of HIV viral variation.